Study hints at pneumonia risk with resistant flu viruses

Dec 31, 2008 (CIDRAP News) – A newly published analysis of oseltamivir-resistant influenza viruses collected last winter in Norway hints that they may increase an infected person's risk of pneumonia and sinus infections, but the small number of patients in the study means the finding is no more than a hint at this point.

Increased resistance to oseltamivir (Tamiflu) in influenza A/H1N1 viruses emerged last winter in Europe, the United States, and elsewhere, and was first observed in Norway. Because nearly all H1N1 viruses tested in the United States so far this winter have shown resistance, the Centers for Disease Control and Prevention earlier this month changed its recommendations for use of antiviral drugs in flu patients. H1N1 is one of the three influenza subtypes that typically circulate each winter.

Writing in Emerging Infectious Diseases, Norwegian researchers report that they collected and analyzed H1N1 viruses from 272 patients and determined that two thirds of the viruses were resistant to oseltamivir. Patients infected with the resistant variety had higher rates of pneumonia and sinusitis than those who had the susceptible viruses. But because of the small sample size, the differences were not statistically significant.

"Because of our limited sample size, the precision of our estimates is low, but they do indicate findings that warrant further investigation," write the researchers, led by Siri H. Hauge of the Norwegian Institute of Public Health in Oslo. Their study was published online ahead of print.

The researchers tested the oseltamivir susceptibility of all H1N1 viruses collected during Norway's 2007-08 flu season and also gathered data on the patients by sending questionnaires to their physicians. The viruses were obtained from primary care clinics and hospitals during routine flu surveillance. Norway's national influenza center tested the viruses for the mutation (called H274Y) that confers oseltamivir resistance, and many of the isolates were sent to the Health Protection Agency in London for further genetic analysis.

H1N1 infections were confirmed in a total of 297 patients during the flu season, and resistance profiles were obtained for 272 of these, according to the report. Of the 272 isolates, 183 (67.3%) showed oseltamivir resistance.

Questionnaires provided information for 265 of the patients, but response rates for specific questions varied, the report says. The median age for patients with resistant viruses was 31, versus 21 for those with susceptible viruses. From the available responses, none of the patients had received antiviral treatment in the 2 weeks before they fell ill. There was no clear link between having a predisposing disease (diabetes, heart disease, lung disease, or immune deficiency) and infection with a resistant virus, and resistance was not associated with any particular symptom.

Of 241 patents for whom information was available, 58 (24.1%) had at least one complication, but there was no significant difference in overall complication rates (24.4% versus 22.1%) or in hospitalization rates (15.8% versus 19.5%) between those with resistant and susceptible viruses.

However, the differences for pneumonia and sinusitis in particular were greater, though not significant. Patients with resistant viruses were more likely to have pneumonia (9.2% of 153 patients versus 2.9% of 69; relative risk, 3.2; 95% confidence interval [CI], 0.7 to 13.7) and sinusitis (6.2% of 145 versus 3.0% of 67; relative risk, 1.7; 95% CI, 0.4 to 7.5).

The authors comment that sicker patients are more likely to be tested for flu, but because physicians didn't know the resistance pattern of the virus at the time of sampling and reporting, their findings regarding pneumonia and sinusitis are not likely to be due to selection bias.

The researchers also observe, "The prevalence of oseltamivir-resistant viruses reported in Europe throughout the 2007-08 influenza season clearly shows that this resistant mutation is stable and that these viruses sustain their fitness and ability to spread among persons."

Disease expert Michael T. Osterholm, PhD, MPH, called the findings interesting but cautioned against drawing any conclusions about a link between oseltamivir resistance and pneumonia risk. He is director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of CIDRAP News.

The patients with the resistant viruses were somewhat older than the others, which would typically signal a higher risk for pneumonia, he observed, adding, "With such small numbers it's difficult to make any concrete statements about a relationship between clinical presentation and resistance status. It serves as an important piece of information for evaluating the current situation in the US to see if there might be some mechanism that accounts for clinical presentation and resistance."